Cardiovascular diseases (CVD) are the number one cause of death and are projected to remain the leading cause of death. Among CVD, worldwide prevalence estimates for hypertension, or high blood pressure (BP), may be as much as 1 billion individuals. Hypertension is the single biggest risk factor for stroke and heart attacks, and a primary or contributing cause of death for 348,000 Americans in 2008, or nearly 1,000 deaths a day. With prevalence higher than 33% in United States, hypertension remains an increasingly important medical and public health issue. We have previously reported that DOCA-salt-induced neurogenic hypertension is associated with a reduction of Angiotensin Converting Enzyme 2 (ACE2) and an increase in A Disintegrin And Metalloprotease 17 (ADAM17) (aka TNF? convertase) activity in the hypothalamus. Blocking Angiotensin-II type 1 receptors or silencing ADAM17 in the CNS prevented hypertension. The central hypothesis of this proposal is that activation of ADAM17 on neurons involved in BP regulation leads to dysautonomia and contributes to the development of hypertension. The immediate goal of this application is to characterize the role of ADAM17-expressing neurons in the control of cardiovascular function and during the development of hypertension through the following aims. Specific Aim 1: Identify the critical brain regions mediating ADAM17-driven neurogenic hypertension. We propose to study putative candidates of ADAM17-mediated neurogenic hypertension among key brain regions (i.e PVN, nTS and RVLM) involved in BP regulation. Specific Aim 2: Determine the main mechanism driving ADAM17-mediated neurogenic hypertension. We plan to assess the contribution of ACE2 loss and TNF? formation to the maintenance of neurogenic hypertension utilizing the combination of transgenic mice and Archaerhodopsin-mediated optogenetics. Beyond demonstrating the feasibility of measuring instantaneous contribution of specific neuronal groups to BP in conscious animals by causing a short-lasting inhibition of their activity, these optogenetic experiments will allow us to identify the main location and mechanism of ADAM17-driven neurogenic hypertension with the ultimate goal of identifying selective new targets for the treatment of this disease.